Circadian rhythms in organs, tissues and cells, which are entrained to the 24-h day by cycles of light and nutrition, lose amplitude and phase stability with age. Humans exhibit an endogenous circadian rhythm in glucose tolerance and respond to meals with higher glucose levels at night. GWAS implicate circadian genes in the risk of T2D, and some key components of the circadian molecular clock (CMC) that regulate glucose metabolism. We have found that acute circadian misalignment in young adults leads to higher post-prandial glucose despite elevated insulin, whereas recurrent circadian disruption (RCD) combined with sleep restriction leads to higher post-prandial glucose and decreased insulin, even when the meal is consumed at an appropriate circadian phase. This may explain why night workers are at increased risk of conditions associated with metabolic aging: obesity, metabolic syndrome and diabetes. Since circadian dysregulation is common in older Americans, 3 million of whom work at night, it is critical for development of targeted therapies to understand the metabolic risks associated with RCD, even when sleep loss is minimized. Project 1 will evaluate the impact of RCD on glucose metabolism in older adults. Whereas chronic sleep loss and acute circadian misalignment induce insulin resistance, we hypothesize that RCD disrupts coordination among central and peripheral CMCs, thereby profoundly impairing pancreatic P-cell responsiveness and inducing insulin resistance. By comparing responses of older participants on a forced desynchrony (T=28h) protocol for a month with those on a 24-h day, we will test the hypotheses that in response to a standard test meal: 1) acute circadian misalignment will induce increase glucose levels, despite increased insulin levels; 2) 3-week history of RCD (while minimizing sleep loss) will induce increased glucose levels accompanied by reduced insulin levels, even when the meal is consumed at a normal circadian phase; 3) 3-week history of RCD (while minimizing sleep loss) will alter the waveform and amplitude of the circadian Cortisol rhythm; and that 4) re-imposing a 24-h light-dark/meal schedule for 1 week will re-entrain circadian rhythms, normalizing the Cortisol rhythm and the glucose and insulin responses to a standardized meal. This Project will contribute to understanding the distinct metabolic risks from circadian disruption, laying the groundwork for research designed to develop therapies targeted to reduce the risk of obesity, metabolic syndrome and diabetes, and enhance the health and quality of life of older Americans whose circadian rhythms are disrupted by age-related changes, irregular schedules, and/or night shift work.